Impact of the aging niche on cancer phenotypes probed using mouse cancer models produced by somatic engineering.

摘要 衰老是癌症发展的最大风险因素，但其生理和分子机制 这种关系背后的原因仍然鲜为人知。毫无疑问，一个促成因素是时间--即 单个细胞需要数年或数十年的时间才能获得足够的突变来引发显性疾病。然而， 其他因素当然也起到了作用，包括与年龄相关的细胞新陈代谢变化，DNA损伤反应， 免疫细胞功能，以及衰老细胞的丰度。在了解这些因素如何影响 肿瘤发生学将揭示改善癌症干预和治疗的策略，以及研究癌症的简便模型 在老年动物中缺乏。为了应对这一关键挑战，我们将体细胞组织工程学 方法将致癌基因突变直接导入老龄小鼠的脏器中，从而省时省力 多等位基因工程小鼠模型(GEMM)的交叉和老化队列的成本。我们 已经开发出一系列针对不同靶器官和癌症的“非生殖系转基因生物”(NGEMM) 基因分型，并表明由此产生的癌症概括了分子和组织学特征 相应的人类疾病。我们还用衰老的小鼠生产了nGEMM，并表明 发展中的肿瘤有不同的免疫浸润物，具有不同的肿瘤监视能力。这项建议 将nGEMM的独特功能与最先进的组织分析相结合，以评估 老年环境对癌症在不同器官环境中表现的影响，并将结果与 饮食或遗传因素将生物年龄与实际年龄分开。实施高级 单细胞方法将产生肿瘤发展过程中细胞类型和细胞状态差异的详细图像 老龄动物和扰动研究将探索肿瘤细胞年龄的内在和外在因素- 相关表型。拟议的实验将受益于我们在癌症生物学方面的专业知识与 这是劳拉·尼德霍费尔博士的研究，她在研究生物衰老方面拥有丰富的经验。我们的研究将 建立广泛可移植的模型，以研究老年小鼠的癌症，其广度和速度与以前相同 不可能的，并对表观遗传和生理过程如何与年龄联系产生新的见解 导致癌症发病率和/或进展的增加。

SUMMARY Aging is the greatest risk factor for cancer development, yet the physiological and molecular mechanisms underlying this relationship remain poorly understood. Undoubtedly, one contributing factor is time – i.e. the years or decades needed for a single cell to acquire sufficient mutations to trigger overt disease. However, other factors certainly play a role, including age-related changes in cell metabolism, DNA damage responses, immune cell function, and the abundance of senescent cells. While understanding how these factors influence tumorigenesis will reveal strategies to improve cancer intervention and treatment, facile models to study cancer in aged animals are lacking. Addressing this critical challenge, we incorporate somatic tissue engineering methods to introduce oncogenic mutations directly into the organs of aged mice, thereby obviating the time and costs of intercrossing and aging cohorts of multi-allelic genetically engineered mouse models (GEMMs). We have developed a range of such “non-germline GEMMs” (nGEMMs) of different target organs and cancer genotypes and shown that the resulting cancers recapitulate molecular and histological features of the corresponding human disease. We have also produced nGEMMs using aged mice and shown that the developing tumors have distinct immune infiltrates with different tumor surveillance capabilities. This proposal combines the unique capabilities of nGEMMs with state-of-the-art tissue analyses to assess the contribution of the aged environment to cancer manifestation in different organ contexts and compares results to settings in which dietary or genetic factors uncouple biological age from chronological age. Implementation of advanced single cell methods will produce a detailed picture of cell type and cell state differences in tumors developing in aged animals and perturbation studies will explore tumor cell intrinsic and extrinsic factors underlying age- related phenotypes. The proposed experiments will benefit from combining our expertise in cancer biology with that of Dr. Laura Niedernhofer, who has extensive experience in studying organismal aging. Our studies will establish broadly portable models for studying cancer in aged mice at a breadth and pace that was previously impossible and produce novel insights into how the epigenetic and physiological processes linked to age contribute to an increase in cancer incidence and/or progression.